Article

Hydrolysis of nerve agents by model nucleophiles: a computational study.

Department of Chemistry, The Ohio State University, 100 W. 18th Avenue, Columbus, OH 43210, USA.
Chemico-Biological Interactions (Impact Factor: 2.98). 06/2008; 175(1-3):200-3. DOI: 10.1016/j.cbi.2008.04.026
Source: PubMed

ABSTRACT Density functional theory calculations were employed to study the reaction of five nerve agents with model nucleophiles, including EtX(-) and EtXH (X=O, S, Se) for serine, cysteine and selenocysteine, respectively. Calculations at the B3LYP/6-311++G(2d,p) level of theory predict an exothermic reaction between ethoxide and all of the nerve agents studied. As compared to EtO(-) as a nucleophile, these reactions become approximately 30 kcal/mol more endothermic for EtS(-), and by approximately 40 kcal/mol for EtSe(-). The equivalent reactions with the neutral nucleophiles (EtXH) were more endothermic. The effect of solvation on the reaction thermochemistry was determined using a polarizable continuum model simulating the dielectric constant of chloroform. While there was a large exothermic shift for reactions involving charged nucleophiles with solvation modeling, the corresponding shift was minimal for the reaction with neutral nucleophiles.

0 Bookmarks
 · 
105 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms of the aging process of tabun-conjugated acetylcholinesterase were explored using density functional theory calculations. The free energy surfaces were calculated for O-dealkylation (C–O bond breaking) and deamination (P–N bond breaking) pathways for the aging process of tabun-conjugated acetylcholinesterase as suggested by mass and crystallographic studies. Initially, the calculations were performed using tabun-conjugated serine (SUN) molecule. O-dealkylation mechanism proceeds via one-step SN2 type process, whereas the deamination process proceeds via two steps addition–elimination reaction at the phosphorus center of SUN molecule. The recent proposal of another deamination mechanism using human butyrylcholinesterase (hBChE) conjugated with N-mono methyl analogue of tabun (TA4) has also been explored (Nachon et al. in Chem Biol Interact 187:44–48, 2010). The rate-determining activation barrier calculated for this deamination mechanism (26.3 kcal/mol) was comparable with O-dealkylation process (26.9 kcal/mol) with B3LYP/6-31+G* level of theory. To examine the influence of catalytic residue His447, additional calculations were performed with imidazole group of His447 residue. The incorporation of imidazole group of catalytic residue His447 showed marked decrease in the free energies of activation for all the studied aging processes of tabun-inhibited serine. The aging mechanisms have been explored with TA4-inhibited serine, and calculated results showed that the deamination with the rearrangement process is markedly preferred in this case, which supports the Nachon et al. proposal based on the crystallographic studies.
    Theoretical Chemistry Accounts 03/2012; 131(3). · 2.14 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The influence of citric acid under different pH conditions towards the morphology of sodium chloride was investigated employing DFT calculations. Prior to any analysis, conformational search of citric acid and its three dissociated forms was performed with molecular mechanics MM2* and DFT (B3LYP/6-31+G*) methods in the gas and aqueous phase. The low energy conformers generated in the aqueous phase were found to be in good agreement with the available crystal structures. The calculated higher composition of citric acid at natural pH ¼ 0.75 i.e., a 0 ¼ 0.99 is not effective for the habit modification of sodium chloride. Quantum chemically derived molecular electrostatic potential (MESP) showed the possible sites of citric acid and its dissociated forms with the estimated deepest V min values and their magnitudes provide an insight for their interaction with the crystal surfaces of sodium chloride. The composition analysis and MESP derived data suggest that the dissociated forms of citric acid at higher pH values are responsible for the change in habit of sodium chloride from cubes to octahedrons. Further, slab model calculations performed to mimic the surfaces of sodium chloride with DFT methods using a conductor-like screening model in the aqueous phase (COSMO) for the interactions of citric acid and dihydrogen citrate validates that there is no preference for the {111} plane of NaCl with citric acid. However, a significant preference was seen with dihydrogen citrate, which quantifies the MESP analysis and corroborates the dependence of morphology on the pH of the solution.
    CrystEngComm 01/2009; 11:2660. · 3.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Organophosporous VX agent O-ethyl S-(2-diisopropylethylamino)ethyl methylphosphonothioate is one of the main nerve agents. For this reason, the search for ways to deactivate it is very important. In this work, hydrolysis and adsorption reactions of a VX-like compound (O,S-dimethyl methylphosphonothioate, DMPT) on the MgO(001) surface were studied by density-functional theory (DFT) using periodic boundary conditions. A degradation reaction mechanism was proposed and theoretically investigated on two types of MgO(001) surfaces: the terrace and the Al-doped. Conformations, free-energy differences, transition states, reaction barriers, and minimum-energy paths were computed. We found that the P–S bond, related to the agent toxicity, breaks via hydrolysis occurring spontaneously throughout the analyzed temperature range, 100–600 K. In the dissociative chemisorption of the DMPT molecule, the formation of the MgO:[PO(CH3)(OCH3)]+[SCH3]− intermediate is catalytically favored from a temperature of about 335 K for the Al-doped surface, a value considerable smaller than the 500 K value for the same process on the terrace. At 335 K, the dissociation fragments on the Al-doped surface are less stable in comparison to the hydrolysis products. The possible reconstitution of the P–S bond on both surfaces does not occur according to kinetic analysis; however, the electronic energy barrier for the direct dissociation reaction on the Al-doped sites is about 49.0 kJ/mol lower than the value for the terrace. After recombination with the OH– and H+ ions, the HOPO(CH3)(OCH3) and HSCH3 products do not accumulate on either surface because these molecules desorb below the DMPT dissociation temperatures. The Al-doped sites of MgO(001) are thus more active in the catalytic hydrolysis process of the VX-like organophosphorus compound than is the nondoped surface.
    The Journal of Physical Chemistry C 10/2013; 117(40):20791–20801. · 4.84 Impact Factor

Preview

Download
0 Downloads
Available from